Vasculogenic mimicry (VM) describes a process by which tumor cells formed a novel microcirculation pattern in an endothelial cell-free manner. Clinically, VM is associated with aggressive phenotype and poor patient survival. However, the current models for investigating VM include 2D monolayer cultures, Matrigel-based cultures, and animal models, each of which has limitations. Matrigel-based models often exhibit batch-to-batch variations, while in vivo tumor models currently produce insufficient amounts of VM. There is currently no suitable tumor model to discover new therapeutic targets against VM. Herein, we establish an extracellular matrix (ECM)-based engineered tumor model in vivo and in vitro. In this study, we demonstrate that matrix proteins enhanced the VM formation in the engineered xenograft model. Furthermore, we also investigated the role of collagen/fibronectin (FN) in melanoma progression and VM formation. Compared with cells cultured on TCPS plates, the B16F10 cells cultured on collagen/FN coated plates showed increased proliferation and stemness, and significantly enhanced invasion and formation of VM networks. Molecular mechanism analysis showed that Integrin/VE-cadherin/EphA2/PI3K/MMP-2 signaling pathways are responsible for VM formation. Our results indicate that collagen/FN matrix plays an important role in VM formation in melanoma, suggesting that ECM protein is a potential therapeutic target for anti-VM therapy for melanoma.

中文翻译：

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工程设计的体内和体外肿瘤模型重现了黑色素瘤中的血管生成拟态特征

血管生成拟态（VM）描述了肿瘤细胞以无内皮细胞的方式形成新型微循环模式的过程。临床上，VM 与侵袭性表型和患者生存率低相关。然而，目前研究 VM 的模型包括 2D 单层培养物、基于基质胶的培养物和动物模型，每种模型都有局限性。基于基质胶的模型经常表现出批次间的差异，而体内肿瘤模型目前产生的 VM 量不足。目前尚无合适的肿瘤模型来发现针对 VM 的新治疗靶点。在此，我们在体内和体外建立了基于细胞外基质（ECM）的工程肿瘤模型。在这项研究中，我们证明基质蛋白增强了工程异种移植模型中 VM 的形成。此外，我们还研究了胶原蛋白/纤连蛋白 (FN) 在黑色素瘤进展和 VM 形成中的作用。与在TCPS平板上培养的细胞相比，在胶原/FN包被的平板上培养的B16F10细胞显示出增加的增殖和干细胞性，并且显着增强的侵袭和VM网络的形成。分子机制分析表明Integrin/VE-cadherin/EphA2/PI3K/MMP-2信号通路参与VM的形成。我们的结果表明胶原蛋白/FN 基质在黑色素瘤 VM 形成中发挥重要作用，表明 ECM 蛋白是黑色素瘤抗 VM 治疗的潜在治疗靶点。